MBD2 is thought to play a role in the silencing of certain genes by recruiting Mi2/NuRD repressor complex. To best study how the Mi2/NuRD complex plays a role in the silencing of ?-globin, we have set out to study this model in human hematopoietic progenitor cells. When cultured on a differentiation medium, these cells mimic the hemoglobin switch that occurs during development. Because knocking down Mi2 on mouse erythroid cells bearing the human -locus had several fold greater effect than knocking down MBD2, Mi2 will be studied to determine if it acts outside of the MBD2-NuRD complex. Furthermore, the role of MBD2 in ?-globin gene expression will also be studied in the context of a sickle cell mouse model. By crossing MBD2-/- mice with sickle cell mice, we will determine whether ablation of MBD2 is able to ameliorate the effects of this condition. This project has clinical significance for patients with hemoglobinopathies (e.g., sickle cell anemia and beta thalassemia), where induction of ?-globin expression has a therapeutic effect. If knocking down MBD2 in an in vivo model produces a considerable change in the expression of ?-globin, as has been previously shown in vitro, this makes such protein a good target in these diseases. Moreover, by characterizing the components and interactions of the methylcytosine protein binding complex we could potentially identify other possible targets. This targeted approach may yield a more tissue-specific treatment to conditions such as -thalasemia, providing clinicians with better options than current treatments. Studying specific protein interactions and mechanisms of gene expression has led to the development of highly successful targeted treatments (notably, Gleevec for Chronic Myelogenous Leukemia). This is the goal of my research, to build a better understanding of processes that will have a great impact on the future treatments. PUBLIC HEALTH RELEVANCE: Inherited hemoglobinopathies such as beta thalassemia and sickle cell anemia affect a large percentage of the population in the United States. The lack of effective treatments without toxic effects to patients supports the need for new treatments to increase the expression of fetal hemoglobin, as this is beneficial to these patients. The results from this study could provide newer and better treatments for these patients.